Work

Jet lag-induced circadian disruption elevates glioma risk by altering molecular profiles in distinct brain regions

Year: 2025

Type: article

Abstract: To investigate the mechanism underlying chronic jet lag (CJL)-induced circadian disruption stimulating glioma-related gene expression across distinct brain regions, and to examine the regulatory role of core clock genes in modulating neural oncogenic susceptibility. This experiment was initiated with the establishment of an animal model of CJL (6-h light-cycle advances every 2 days for 10 or 30 days) in wild-type and clock gene-deficient mice (Bmal1−/−, Per1/2−/−, and Cry1/2−/−). Then, tissues harvested from six neural regions (i.e., hippocampus, prefrontal cortex, striatum, hypothalamus, raphe nuclei, and nucleus accumbens) were subjected to tissue-specific qPCR profiling of cancer-related genes (C-MYC, MDM-2, GADD45A, and p53). Additionally, bioinformatics analyses (DAVID, ConsensusPathDB) was employed to identify pathway interactions, with statistical validation using ANOVA and t-tests. CJL induced brain region-specific dysregulation of oncogenic pathways, with marked activation of oncogenes (C-MYC↑, and MDM-2↑) in hypothalamic and striatal regions, while suppression of tumor suppressors (GADD45A↓, and p53↓) in hippocampal and cortical regions. Clock gene mutations amplified these effects, particularly in Bmal1−/− mice, indicating core clock components as critical modulators of neural oncogenesis. Meanwhile, sex-dependent differences emerged in cerebellar tumor suppressor responses to CJL. Besides, pathway analysis revealed circadian-glioma crosstalk through p53-mediated apoptosis and cell cycle regulation. Chronic circadian disruption acts as a brain region-specific oncogenic stressor, driving transcriptional reprogramming of cancer pathways in a clock gene-dependent manner. Mechanistically, our study may establish a relationship of circadian dysfunction with glioma risk, underscoring the necessity for sex-stratified chronotherapeutic approaches in neuro-oncology. The study provides evidence that chronic jet lag (CJL) can lead to region-specific changes in glioma-related gene expression, potentially increasing the risk of glioma. The present study underlines the importance of understanding the mechanism of circadian rhythm disruptions, such as those induced by CJL, in inducing cancer progression, specifically in the context of brain tumors. Our study unveils potential interaction between clock genes and cancer-related genes, as well as the differential gene expression patterns in various brain regions, highlighting the complexity of relevant molecular mechanisms in CJL-induced glioma risk.

Source: Discover Oncology

DOI: 10.1007/s12672-025-03253-0